This invention relates to the prevention of infections associated with medical devices disposed long-term in a body.
More particularly, the invention provides a coating containing anti-bacterial agents for slow release into the environmental space with which the device is in contact. It is to be applied on healthcare devices such as urinary latex or other polymeric catheters, urethral stents for residence within a portion of the body through which aqueous biological fluids pass.
A medical device with anti-bacterial property is intended to prevent the spreading and penetration of the bacteria from the place of the entrance of the medical device into the body of the patient and consequent infection. The purpose of this invention is to create a method and composition for the treatment of the outer and/or the inner surface of the medical device for rendering it anti-microbial property without any change in the performance and properties of the device.
Catheter-associated urinary tract infection is the most common nosocomial infection and is a major problem with severe consequences, that cause prolongation of hospitalization time and contribute to patient suffering. This problem becomes especially critical for patients using a long-term indwelling urinary catheter. The latter, if it remains in the body for a prolonged time, is the basis for initial adherence of microorganisms to the device's polymeric surface with consequent growth of bacteria on the catheter surface and production of bio-film.
Anti-microbial therapy alone, generally, is not sufficient to cure the patient of these infections, and frequent replacement of the catheter remains the only method for possible treatment of the sick person.
Development of catheters with anti-adhesive and/or anti-infective properties is a plausible approach to the prevention of such infections. Anti-adhesive polymeric catheters may prevent adherence of microorganisms to the medical device surface; anti-infective polymers contain anti-microbial substances which are incorporated into the polymer's matrix or bound to the polymer's surface and act as a drug release system that leads to reduction or prevention of infection.
The problem of producing urinary catheters with anti-infective property and slow release ability is very complicated. There are many patents and research papers that offer different versions of solutions to the mentioned problem.
The anti-bacterial properties may be imparted to the catheter by two methods.
The first is using the polymers with anti-bacterial properties that are delivered by insertion of an anti-bacterial agent or medicine into the polymer matrix through process of production of medical device. This method has severe restrictions—the structure of the polymer matrix is very dense and hinders the migration of the anti-bacterial agent from inner space to outer surface of device and as a result—negligible anti-bacterial effect is achieved. In addition anti-bacterial agents and/or medicines should be compatible with the substances used for producing the polymer and all the ingredients must be stable at the time of production. The production usually requires high temperatures and pressure.
The second method of rendering anti-bacterial properties to the medical devices consists of the treatment of the medical device with anti-microbial agent by one of following ways—dipping, spraying, spreading and linking the former to the polymer surface of the medical device. However, almost all the medical devices are made from synthetic polymers such as polyethylene, polypropylene, polytetrafluoroethylene, polyvinylchloride, polymethylmethacrilate, polyurethane or latex (natural or synthetic rubber) and have a smooth, hydrophobic surface without any active chemical groups able to interact with an antibacterial agent. Thus after treatment some quantity of the anti-bacterial agent remains on the surface of device but it cannot be linked and does not provide a drug-release effect.
Detailed discussion of catheter related infections and the means of prevention was a topic at the 1st National Workshop on Catheter Infections in Cologne (Germany) in 1994.
Prior art ways of rendering the anti-microbial ability to polymeric medical devices are described in the following patents and articles.
U.S. Pat. No. 5,019,096 offers a method of preparing an infection-resistant medical device comprising one or more matrix-forming polymers selected from the group, consisting of biomedical polyurethane, silicones and biodegradable polymers and anti-microbial agent especially a synergistic combination of a silver salt and chlorhexidine (or its salts) wherein the matrix is effective to provide controlled release of anti-microbial agent within a portion of the human body.
U.S. Pat. No. 5,599,321 claims a sustained release bactericidal cannula or catheter for residence within a portion of a human body, that has a polymer matrix and an anti-bacterial agent residing within. The polymer matrix includes cured silicone rubber and within the antibacterial agent—finely divided nitrofuran compound which can effectively prevent proliferation of certain bacteria. The anti-microbial agent can diffuse out of the polymeric matrix into an aqueous biological environment when the polymeric matrix comes into contact with it.
U.S. Pat. No. 5,089,205 claims the process for imparting enhanced anti-microbial properties to medical devices that involves dipping the device into a latex composition and prior to curing or heating dipping the already coated forms into a second composition containing an anti-bacterial agent and thereafter curing the finally produced device such as gloves, before stripping from a forming apparatus.
One of the widely developed methods of enhancement of the anti-bacterial properties of medical devices (catheters) from synthetic polymers is based on the usage of metals and especially silver which possesses anti-bactericidal potency.
A Division of Bard Medical introduced the Bardex J.C. Catheter that is produced by sputtering micro-particles of silver to form a thin layer on the surface. Bardex J.C. Catheter material yields negligible zones of inhibition for bacteria but no catheter-associated urinary tract infections occurred during the first three months.
Böswald M. et al determined the antibacterial activity of polyurethane and silicone catheters, containing low concentration of silver, that was introduced by precipitation of silver chloride in the polymer matrix. The method of attaching of bactericidal property comprises swelling of the catheter in methanol, ethanol, isopropanol or acetone and immersing with compounds containing silver in ethanolamine.
U.S. Pat. No. 4,592,920 describes method for the production of anti-microbial catheter with an anti-microbial metal compound powder having particle size to about 30μ in diameter. The comminuted antimicrobial metal compound is suspended in a suspending agent which can be cured to form a catheter or which can be formed to provide a coating on a previously formed catheter.
Impregnation of urological catheter with silver oxide has given inconsistent results. Riley and Johnson found no significant reduction in the rate of bacteriruria, when catheters with silver oxide were evaluated in a large number of patients.
Liedelberg found that silver alloy catheters were significantly more effective in preventing bacteriuria than silver oxide catheters.
The level of anti-microbial activity of silver depends on the chemical structure and the technique used for binding the silver to the catheter matrix. Taking into account very low solubility of silver and its derivatives, the efficacy of this treatment would not be significant.
Many inventors and researchers have tried to find a method of surface treatment of catheters.
U.S. Pat. No. 4,612,337 describes the method of preparing infection-resistant polymeric materials for use outside or within human body which comprises the following sequence of steps: soaking a polymeric material with a solution of an anti-microbial agent such as sodium sulfadiazine, oxacilline, dissolved in an organic solvent, thereafter soaking the polymeric material in an organic solvent such as ethanol for a metal salt such as silver nitrate, resoaking the polymeric material with the solution of antimicrobial agent dissolved in the organic solvent thereafter. The polymeric material is dried after each step, finally the treated catheter has on the surface a coating of antimicrobial agent—silver sulphadiazine.
Cook Critical Care manufactures catheters (polyethylene) that are treated with antibiotic-cefazoline which is bonded to the surface of the catheter by the cationic surfactant—tridodecylmethylammonium chloride (TDMAC).
Cook Critical Care also produces the central venous catheters impregnated with a combination of two antibiotics: minocycline and rifampin, that are bonded to the surface of the catheter through TDMAC. Both antibiotics have broad spectrum activity against various nosocomial pathogens.
The ionic linking of TDMAC to hydrophobic uncharged surface of polyethylene is doubtful due to the absence of any active groups in polyethylene.
Pugach developed an antibiotic liposome (ciprofloxacin liposome) containing hydrogel for external coating of silicone Foley catheter. The treated catheter shows 30% decrease in cases of bacteriuria compared to untreated catheters.
Hashimoto et al developed antibacterial and antiadherent coating for silicone catheters on the base of the mixture of soybean lecithin as anti-adherent component, silver citrate as anti-bacterial agent and liquid silicone. The treated urinary catheter has anti-microbial activity to Gram-positive and Gram-negative bacteria.
Simhi E. treated the silicone rubber catheter with TA adhesive antibiotic that decreases adhesion and initial growth of Esherichia coli. 
U.S. Pat. No. 4,539,234 describes a process for producing an urethral catheter capable of preventing urinary tract infections, which comprises of forming a film having functional groups capable of being converted into ion-exchange groups by hydrolysis on the inside and/or outside wall of urethral catheter composed of olefin polymer, diene or silicone polymer. The ion-exchange groups are carboxyl groups that are obtained by reacting a copolymer of maleic acid anhydride and a copolymerizable compound with a polyfunctional compound having hydroxyl groups under a condition of an excess amount of the copolymer and thereafter hydrolyzing the acid anhydride groups.
Johnson J. R. et al compared the anti-microbial activity of a nitrofurazone-coated urinary catheter (NFC) and a silver hydrogel urinary catheter (SHC) and found that in-vitro NFC is markedly superior that the SHC in some respects.
Maki et al studied a novel triple-lumen polyurethane central venous catheter coated with silver sulfadiazine and chlorhexidine and found that antiseptic coated catheters were two-fold less likely to be colonized than untreated and four-fold less likely to produce bacteremia.
All the catheters with coating, impregnated with an anti-bacterial agent and containing an anti-bacterial agent within polymer matrix, develop their anti-bacterial action gradually—at first by contact with environmental wet medium there is a high initial release rate, the so-called “burst effect”, depending on a number of parameters: mass, distribution and solubility of the anti-bacterial agent within the polymer or on its surface, strength of adhesion, degree of swelling of the film on the surface of the medical device, properties of the components of the used composition. Usually the rate of release of an antibacterial agent at the initial period is relatively high. The second continuous period is controlled by the structure of the polymeric matrix, if the antibacterial agent is within it, or by the degree of swelling of the coating on the surface.
A large part of the “burst effect” could be removed simply by cleaning the catheter surface.
The described methods of enhancement of the anti-bacterial property of the medical device, in particular catheters, are not likely to give a complete solution to the problem due to a multiplicity of factors defining the processes of adhesion and release of anti-bacterial agent, for example the compatibility of anti-bacterial agent and the synthetic polymeric device, and their other properties.
It is therefore one of the objects of the present invention to obviate the disadvantages of prior coatings and to provide a catheter with a coating that releases an anti-bacterial agent in a predictable manner.
It is a further object of the present invention to provide a method for the manufacture of the coated catheter.